Raltegravir Activity In Lymphoid Tissues

This study has been withdrawn prior to enrollment.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Timothy W. Schacker, University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT00863668
First received: March 16, 2009
Last updated: October 24, 2011
Last verified: October 2011

March 16, 2009
October 24, 2011
March 2009
March 2010   (final data collection date for primary outcome measure)
  • Rate of HIV mRNA Decline Measured in Peripheral Blood [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Rate of HIV mRNA Expression Decline Measured in Lymphatic Tissues [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • CD4+ T Cell Number Increase in Peripheral Blood Over Time [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • CD4+ T Cell Increase Quantified in Lymphatic Tissues Over Time [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00863668 on ClinicalTrials.gov Archive Site
Intracellular concentrations of antiretroviral drugs [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Raltegravir Activity In Lymphoid Tissues
Decay Kinetics of HIV With the Integrase Inhibitor Raltegravir

The reduction with antiretroviral therapy (ART) of HIV RNA in blood, and HIV RNA in infected cells and in viruses associated with the follicular dendritic cell (FDC) network in lymphatic tissues, typically follows a two-phase pattern of decline. The half-life of the first-phase is about 1 day and that of the second phase is about 14 days, with comparable estimates for first-phase decay in SIV-infected rhesus macaques.

While substantial evidence supports the current view that first-phase decay reflects the death of activated CD4+ T cells infected before ART was begun, the sources of viral RNA in the second phase have not as yet been conclusively established. Possible sources of viral RNA that have been invoked in mathematical models, or for which there is experimental evidence, include longer-lived infected cells such as macrophages and resting CD4+ T cells, dissociation of virus from the FDC network, and productively infected CD4+ T cells that are not subject to clearance by host immune responses because of waning levels of HIV antigen.

Raltegravir (MK-0518) belongs to a new class of integrase inhibitors that potently suppress HIV and SIV replication, and reportedly markedly alters the second phase HIV decline in a way that challenges the current view that longer-lived infected cells are the source of virus in this phase. While mathematical modeling of decay of HIV RNA in blood was most consistent with 1) cells newly infected by long-lived cells, or 2) from activation of latently infected cells with full-length unintegrated HIV DNA as a source of second phase virus, we think the data are also quite consistent with the greater efficacy of integrase inhibitors in a particular cell type and/or anatomic site such as the gut.

In this protocol we will test the hypothesis that the rapid decrease in HIV replication associated with raltegravir is due to a more complete suppression of viral replication in lymphatic compartments such as lymph nodes and gastrointestinal lymphatic tissue. We will also investigate compartment-specific intracellular levels of raltegravir to potentially explain differences in changes in these compartments.

The study will evaluate rates of HIV elimination in peripheral blood in comparison to secondary lymphatic tissues, including inguinal lymph nodes (LN) and gastrointestinal lymphatic tissues (GALT). HIV-infected patients who are antiretroviral therapy (ART) naive and fit criteria to initiate ART will be randomized to either Truvada (tenofovir/emtricitabine) + Sustiva (efavirenz - 600mg qDAY orally - standard of care) or Truvada + Isentress (raltegravir - 400mg BID orally).

Patients will have a blood draw, a colonoscopy with biopsies, and inguinal lymph node excision at days 0, 2, 7, 14, and week 52. Plasma HIV RNA and CD4+ T cell quantitation will be performed conventionally. HIV mRNA will be quantitated in LN and GALT using in-situ hybridization (ISH). Immunohistochemistry (IHC) will be performed to quantitate changes in CD4+ cell numbers over time in tissues from each respective ART regimen.

Interventional
Not Provided
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Basic Science
  • HIV Infection
  • HIV Infections
  • Drug: Efavirenz + Tenofovir DF/Emtricitabine
    600mg QD for 52 weeks + 300mg/200mg QD for 52 weeks
    Other Names:
    • Sustiva
    • EFV
    • Tenofovir
    • Tenofovir Disoproxil Fumarate
    • TDF
    • Emtriva
    • FTC
    • Truvada
    • Atripla
    • Nucleoside Reverse Transcriptase Inhibitor
    • NRTI
    • Non-Nucleoside Reverse Transcriptase Inhibitor
    • NNRTI
  • Drug: Raltegravir + Tenofovir DF/Emtricitabine
    400mg BID for 52 weeks + 300mg/200mg QD for 52 weeks
    Other Names:
    • Isentress
    • MK-0518
    • Tenofovir
    • Tenofovir Disoproxil Fumarate
    • TDF
    • Emtriva
    • FTC
    • Truvada
    • Integrase Inhibitor
    • Nucleoside Reverse Transcriptase Inhibitor
    • NRTI
  • Procedure: Colonoscopy with biopsies
    Day 0, Day 2, Day 7, Day 14, Week 52
    Other Names:
    • Colonoscopy
    • Biopsy
    • Secondary
    • Lymphatic
    • Tissue
    • Gastrointestinal
    • GALT
    • Peyers
    • Patch
    • Lamina
    • Propria
  • Procedure: Inguinal Lymph Node Excision
    Day 0, Day 2, Day 7, Day 14, Week 52
    Other Names:
    • Secondary
    • Lymphatic
    • Tissue
    • Inguinal
    • Lymph
    • Node
    • LN
    • Excision
    • Biopsy
  • Active Comparator: Efavirenz
    Interventions:
    • Drug: Efavirenz + Tenofovir DF/Emtricitabine
    • Procedure: Colonoscopy with biopsies
    • Procedure: Inguinal Lymph Node Excision
  • Experimental: Raltegravir
    Interventions:
    • Drug: Raltegravir + Tenofovir DF/Emtricitabine
    • Procedure: Colonoscopy with biopsies
    • Procedure: Inguinal Lymph Node Excision
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Withdrawn
10
March 2011
March 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV positive (proven serologically at the time of screen, unless evidence for seroconversion)
  • Evidence of recent (proven seroconversion within 4 months) or acute infection (HIV antibody negative, HIV RNA positive), or CD4 T Cells > 350 in peripheral blood and plasma viral load > 100,000 copies/ml
  • Antiretroviral therapy naive (no prior history of antiretroviral therapy)
  • Negative pregnancy test for eligible women of childbearing potential

Exclusion Criteria:

  • Contraindication to surgical and endoscopic procedures (as judged by the principal investigator)
  • Psychiatric or psychological illness that would make adherence to protocol procedures unlikely
  • Pregnancy
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00863668
0901M57887
Yes
Timothy W. Schacker, University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
Merck Sharp & Dohme Corp.
Principal Investigator: Timothy W Schacker, M.D. University of Minnesota - Clinical and Translational Science Institute
University of Minnesota - Clinical and Translational Science Institute
October 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP